Hematopoietic stem cells (HSC) can give rise to all mature blood cells and can self-renew. The mechanisms involved in the regulation of self-renewal and differentiation, and of the pool size of HSC in vivo are largely unknown. A potentially powerful approach to dissect regulatory mechanisms for HSC in vivo is the investigation of the extensive genetically determined variation in the HSC compartment in inbred mouse strains. Given the potential role of transforming growth factor-beta (TGF-beta) as a negative regulator of HSC in vivo, we investigated whether there is genetically determined variation in the TGF-beta system in inbred mice, and if so, how this genetic variation would impact on the regulation of the hematopoietic stem and progenitor cell compartment. It was found, using approaches that included in vitro culture, analysis of TGF-beta2-deficient mice, and genetic linkage analysis, that TGF-beta2, but not TGF-beta1 or TGF-beta3, is in fact a positive regulator of HSC that is subject to quantitative genetic variation. This positive regulatory effect of TGF-beta2 requires the presence of serum factors. The goal of this proposal is to further define the role of TGF-beta2 in hematopoiesis, and to investigate the role of TGF-beta2 in quantitative genetic variation in the hematopoietic stem and progenitor compartment in inbred mouse strains The specific aims are: Specific aim 1. To investigate the role of TGF-beta2 in hematopoiesis Specific aim 2 To investigate regulation and role of TGF-beta2 expression levels in HSC Specific aim 3 Gene identification of the QTL involved in the regulation of TGF-beta2 signaling